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Evaluation of Biologic End Points and Pharmacokinetics in Patients With Metastatic Breast Cancer After Treatment With Erlotinib, an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor

From the Cancer Therapeutics Branch, Laboratory of Pathology, Medical Oncology Clinical Research Unit, Laboratory of Cellular and Molecular Biology, and Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute; and National Institute of Dental and Craniofacial Research and the Departments of Diagnostic Radiology and Nuclear Medicine, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD

Address reprint requests to Sandra M. Swain, MD, Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, 8901 Wisconsin Ave, Building 8, Room 5101, Bethesda, MD 20889; e-mail: swains{at}mail.nih.gov

PURPOSE: To evaluate changes in epidermal growth factor receptor (EGFR) phosphorylation and its downstream signaling in tumor and surrogate tissue biopsies in patients with metastatic breast cancer treated with erlotinib, an EGFR tyrosine kinase inhibitor, and to assess relationships between biomarkers in tumor and normal tissues and between biomarkers and pharmacokinetics.

PATIENTS AND METHODS: Eighteen patients were treated orally with 150 mg/d of erlotinib. Ki67, EGFR, phosphorylated EGFR (pEGFR), phosphorylated mitogen-activated protein kinase (pMAPK), and phosphorylated AKT (pAKT) in 15 paired tumor, skin, and buccal mucosa biopsies (at baseline and after 1 month of therapy) were examined by immunohistochemistry and analyzed quantitatively. Pharmacokinetic sampling was also obtained.

RESULTS: The stratum corneum layer and Ki67 in keratinocytes of the epidermis in 15 paired skin biopsies significantly decreased after treatment (P = .0005 and P = .0003, respectively). No significant change in Ki67 was detected in 15 tumors, and no responses were observed. One was EGFR-positive and displayed heterogeneous expression of the receptor, and 14 were EGFR-negative. In the EGFR-positive tumor, pEGFR, pMAPK, and pAKT were reduced after treatment. Paradoxically, pEGFR was increased in EGFR-negative tumors post-treatment (P = .001). Although markers were reduced in surrogate and tumor tissues in the patient with EGFR-positive tumor, no apparent associations were observed in patients with EGFR-negative tumor.

CONCLUSION: Erlotinib has inhibitory biologic effects on normal surrogate tissues and on an EGFR-positive tumor. The lack of reduced tumor proliferation may be attributed to the heterogeneous expression of receptor in the EGFR-positive patient and absence of target in this cohort of heavily pretreated patients.

Authors’ disclosures of potential conflicts of interest are found at the end of this article.

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